Amino-substituted tetracyclic compounds

ABSTRACT

The invention discloses novel compounds of the general formula: ##STR1## and salts thereof, in which X stands for oxygen, sulphur, the group &gt;NR 7  or the group --CR 8  R 9  --; 
     R 1 , r 2 , r 3  and R 4  represent hydrogen, hydroxy, halogen, alkyl (1-6 C), alkoxy (1-6 C), alkylthio (1-6 C) or trifluoromethyl; 
     R 5  and R 6  represent hydrogen, alkyl (1-6 C), aralkyl (7-10 C) or together in combination with the nitrogen atom a heterocyclic five- or six-membered ring; 
     R 7  stands for hydrogen or alkyl (1-4 C); 
     R 8  and R 9  stand for hydrogen or methyl, 
     n is the number 0, 1 or 2 and 
     The dotted line means an optional C--C bond, 
     With valuable central nervous system (CNS) activities, especially antidepressant activity.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation of application Ser. No. 651,759 filed Jan. 23,1976, now abandoned which in turn is a division of Ser. No. 463,636filed Apr. 24, 1974, now U.S. Pat. No. 3,950,425.

The present invention relates to novel biologically activeamino-substituted tetracyclic compounds and to processes for thepreparation thereof.

It was found that compounds of the general formula I: ##STR2## as wellas the pharmaceutically acceptable salts thereof, in which X stands foroxygen, sulfur, the group >NR₇ or the group --CR₈ R₉ --;

R₁, r₂, r₃ and R₄ represent hydrogen, hydroxy, halogen, alkyl (1-6 C),alkoxy (1-6 C), alkylthic (1-6 C) or trifluoromethyl;

R₅ and R₆ represent hydrogen, alkyl (1-6 C), aralkyl (7-10 C) ortogether in combination with the nitrogen atom a heterocyclic five- orsix-membered ring;

R₇ stands for hydrogen or alkyl (1-4 C);

R₈ and R₉ stand for hydrogen or methyl,

n is the number 0, 1 or 2 and

The dotted line means an optional C-C bond,

Possess valuable C.N.S. activities. The toxicity of these compounds isexceedingly low.

The compounds according to the invention may be prepared in a mannercommonly used for analogous compounds.

A very easy starting point for the synthesis of the compounds inquestion is a compound of the general formula II: ##STR3## in which R₁,R₂, R₃, R₄ R₄ and X have the meanings mentioned above. The compounds IIare, as far as known, novel compounds.

The starting material II can be prepared in various manners. The mostsimple method to prepare the compound II is the condensation ofvinylmethylketone ##STR4## with a compound of the general formula III:##STR5## in which R₁, R₂, R₃, R₄ and X have the meanings mentionedabove. This condensation reaction in preparing the starting material IIis performed in a suitable solvent, preferably in the presence of abase, such as sodium hydroxide, potassium hydroxide, sodium ethoxide orsodium hydride. An intermediate product formed in this condensationreaction, namely a compound of formula III with γ-keto-butyl moiety atposition 6, can, if desired, be isolated though it is not necessary todo so.

Starting from a compound with formula II the endproducts according toformula I can be prepared in various manners. All these routes are knownper se and are standard procedures commonly used for the preparation ofsimilar compounds.

The method, which can generally be used in preparing the compounds I ofthe invention, consists of the condensation of a compound with thegeneral formula IV: ##STR6## in which R₁, R₂, R₃, R₄, n and X have themeanings specified before and Y represents a suitable leaving group,such as halogen or an etherified or esterified hydroxyl group, withammonia or an amine according to the general formula V: ##STR7## or anacid addition salt thereof, in which R₅ and R₆ have the meanings definedpreviously.

Leaving groups are well defined groups, described in various chemicalhandbooks.

Suitable leaving groups for this condensation reaction are for example atosyloxy group, a mesyloxy group, a p-bromophenyl-sulphonyloxy group, achlorine, bromine or iodine atom.

The compound IV required for this condensation reaction may be preparedfrom the starting material II described before by reducing the ketogroup to a hydroxy group, preferably with metal hydrides such as LiAlH₄,diboran or in particular NaBH₄, followed by converting this hydroxylgroup into the desired leaving group in a conventional manner, forinstance by tosylation, mesylation, reaction with SOCl₂, PCl₅, PBr₃,etc.

Extension of the alkyl chain (from n=0 to 72=1 or can be performed inthe usual way, for instance by treating a compound IV, in which n=0,with a cyanide such as potassium- or sodiumcyanide. The cyanogroup inthe compound thus obtained can either be reduced to the correspondingaminomethylgroup or be hydrolysed to the corresponding carboxyl group.The aminomethyl compound is then treated with nitrous acid at lowtemperature (Piria), whereas the carboxyl compound is reduced. Bothreactions afford the hydroxy-methyl compound. Finally the hydroxy-methylcompound thus obtained is converted into a compound in which thehydroxyl group is replaced by a leaving group.

By repeating the above-mentioned reaction steps, a further extension ofthe alkyl chain is obtained.

The primary amines according to the general formula I can further beprepared by reduction of the cyanide or azide group of compounds withthe general formula VI: ##STR8## in which R represents one of thefollowing moieties: --(CH₂)_(n-1) --CN or --(CH₂)_(n) --N₃, and in whichR₁, R₂, R₃, R₄, X and n have the meanings indicated before. Theseprimary amines can additionally be converted in a conventional mannerinto the corresponding secundary or tertiary amines I.

The reduction is performed in the usual way for this kind of compounds.The cyanide group is preferably reduced by means of methalhydrides,especially lithium-aluminium-hydride, the azide group by a metalhydridesuch as LiAlH₄ or NaBH₄ or by hydrogenation in the presence of a metalcatalyst such as palladium, Raney nickel, etc.

The starting materials with formula VI required in this method can, forexample, be prepared by treating a compound of formula IV with sodium orsodium azide.

A simple and direct method in preparing a compound I (with n = 0)consists of the reaction of the starting material II with the amineaccording to formula V in the presence of a reducing agent. Suitablereducing agents in this connection are metalhydrides, e.g. NaBH₄,LiAlH₄, NaCNBH₃, etc., but preferably formic acid (Leuckart reaction) orhydrogen in the presence of a suitable catalyst, such as palladium,palladium on charcoal, Raney nickel, etc.

This reductive amination is well-known in organic chemistry anddescribed in any chemical handbook.

The primary amines of the invention (with n =0) can further be preparedby reduction of the oxime moiety of a compound of the general formulaVII: ##STR9## in which R₁, R₂, R₃, R₄ and X have the meanings indicatedbefore.

This reduction may be performed by hydrogenation preferably in thepresence of a metal catalyst, or with metal-hydrides such as LiAlH₄.

The compound VII is prepared direct from the corresponding keto compoundII by treating the latter with hydroxylamine in the usual way, orindirect from the keto compound II by reacting it withisoamylnitrite/potassium-t.butoxide yielding the 2-keto-3-oximecompound, followed by a Wolff-Kishner reduction of the keto group.

A very convenient method for the preparation of the compounds I with n ≧1 is the reduction of an amide of the general formula VIII: ##STR10## inwhich R₁, R₂, R₃, R₄, R₅, R₆, X and n have the meanings definedpreviously.

The reduction is carried out in a conventional manner for the reductionof amides, for example with metalhydrides, especially LiAlH₄.

The starting compounds VIII for this reduction can, for example, beprepared by hydrolysis of the cyano-compound of the general formula VI,yielding the corresponding carboxyl compound, which compound isconverted into the corresponding amide in the usual way, for example byhalogenating the carboxyl group affording the acid halide, followed byreacting the acid halide with an amine of the formula V. The primaryamide of formula VIII may, of course, be prepared directly by partialhydrolysis of the cyano-compound VI.

Finally the present compounds of the invention with general formula Imay be prepared by a reduction of the double bond Δ¹(2) of a compoundwith the general formula IX: ##STR11## in which R₁, R₂, R₃, R₄, R₅, R₆,X and n have the meanings mentioned previously.

This reduction is carried out in a conventional manner, for example withmetalhydrides, such as LiAlH₄, etc. or by hydrogenation in the presenceof a catalyst such as palladium, palladium on charcoal, Raney nickeletc.

The starting compounds IX may be prepared in various manners. Forexample, a compound IX with n = 0 (enamine) may be prepared by treatingthe ketone II with an amine of formula V, preferably in the presence ofa Lewis acid, such as AlCl₃, SnCl₄, etc.

A compound IX with n = 1 may be prepared by treating the ketone II withHCN, eliminating the hydroxyl group formed to obtain a double bond andconverting the cyano group in a conventional manner into an aminomethylgroup. Another method consists of the reaction of the ketone II with thereagent (CH₃)₂ S(→O)=CH₂, whereupon the compound thus obtained istreated with the amine V followed by eliminating the hydroxyl groupformed to obtain a double bond.

A compound IX with n = 2 may be obtained by a Wittig reaction, aWittig-Horner reaction, a Reformatski reaction or a reaction withacetonitril caried out on the starting ketone II. Reagents necessary inthese reactions are well-known and described in any chemical handbook,for example: Ph₃ P'CH--B (Wittig), (EtO)₂ --P(→O)--CH₂ --COR' in NaH anda suitable solvent (Wittig-Horner), BrZn--CH₂ --COR' (Reformatski) andCH₃ CN in the presence of sodiumalkoxide, whereby Ph stands for an arylgroup, in particular a phenyl group, B represents a ##STR12## or a groupthat can easily be converted into this aminomethyl moiety, such as acarboxyl group, an esterified carboxyl group, an amide group, a cyanogroup or a hydroxyl group, and R' stands for an esterified hydroxylgroup.

The Reformatski reaction requires an additional step to obtain the Δ1(2)double bond by eliminating the hydroxy group formed, whereas in allmethods in which the amino-moiety is not present already in the reagentused, an additional reaction has to be carried out in order to convertthe moiety present (carboxyl, hydroxy, cyano, amide, etc.) into thedesired amino-moiety.

Most reactions described preparing the starting material IX involve thereduction of a cyano group or an amide group. It is, of course, possibleto reduce these moieties simultaneously with the Al(2) double bondpresent in the molecule.

In all afore-mentioned methods, in which a reduction has been carriedout in the last step of the synthesis or in one or the previous steps,the conjugated double bond between the phenyl nuclei is not reducedunder the usual reaction conditions.

By carrying out the reduction in question under strong reductiveconditions, e.g. by increasing the reaction temperature and reactiontime, by increasing the quantity of the reducing agent and/or performingthe reduction under high pressure, it is possible to isolate also thecompounds I with a saturated C--C bond instead of the C═C bond inparticular where a catalytic hydrogenation with PtO₂ in acetic acid hasbeen used for the reduction.

A more preferred synthesis for the preparation of these "saturated"compounds I consists of the reduction of the compound VII: ##STR13## inwhich R₁, R₂, R₃, R₄ and X have the aforesaid meanings, with sodium orsodiumamalgam in a suitable liquid, such as sodium in isopropanol, or bya hydrogenation in the presence of platinumoxide (Adams catalyst) underthe usual conditions, especially in acetic acid. In this reduction theΔ4a(13b) double bond as well as the oxime moiety are reducedsimultaneously.

The best method for preparation of the compounds I, in which the 4a(13b)bond is saturated, consists of a reduction of the (Δ4a(13b) double bondof the ketone II.

A catalytic hydrogenation of the ketone II with platinum-oxide in asuitable liquid, preferably acetic acid, yields the corresponding4a(13b)-saturated alcohol X quantitatively: ##STR14## in which R₁, R₂,R₃, R₄ and X have the meanings afore-defined. This alcohol X may beoxidized to the 4a(13b)-saturated ketone of the general formula XI:##STR15## in which R₁, R₂, R₃, R₄ and X have the meanings afore-defined.This oxidation may be carried out in a conventional manner, for examplewith manganesedioxide or chromic acid-pyridine complex. A very usefuloxidation is the biphasic one in which a benzenic solution of thealcohol X is shaken with a solution of CrO₃ in acetic acid/watermixture.

All additional reactions described before starting from the"unsaturated" ketone II or the corresponding alcohol, yielding the"unsaturated" compounds I can also be applied to the ketone XI or thecorresponding alcohol X to obtain the 4a(13b)-saturated compounds I. Inother words the ketone XI or the alcohol X can be converted into the4a(13b)-saturated analogues of the compounds IV, VI, VII, VIII or IXfollowed by conversion of these compounds into the 4a(13b)-saturatedcompounds I in the manner described. The ketone XI can further besubjected to the reductive amination as described previously.

A specific series of biologically active intermediates used in thepresent methods for the preparation of the compounds I are compounds ofthe general formula XII: ##STR16## as well as salts and esters thereof,in which R₁, R₂, R₃, R₄, X and n have the aforesaid meaning. Theseintermediates exert potent anti-inflammatory activity. They can beadministered orally, parenterally or locally in a daily dose of from 0.1mg to 10 mg per kg/body weight.

These compounds XII can be prepared in various manners, indicatedalready in this specification. In this connection there is referred tothe hydrolysis of a cyano group and to methods such as the Wittig,Wittig-Horner and Reformatski reactions mentioned previously. In thelatter methods the double bond (Δ1,2) has to be reduced additionally bymeans of a catalytic hydrogenation.

Compounds XII with n = 0 can further be prepared by treating a compoundof formula IV, in which Y stands for halogen, in particular iodine, withmagnesium, after which the magnesium halide thus obtained (Y = MgHal) isconverted into the corresponding carboxyl-compound by treating with CO₂.

Esters of the compound XII are derived from aliphatic, cycloaliphatic,aromatic or araliphatic alcohols with 1-18 carbon atoms, which may besubstituted by hydroxy or halogen groups, especially lower aliphaticalcohols with 1-6 carbon atoms, or phenylaliphatic alcohols with 7-10C-atoms, such as methanol, ethanol, isopropanol, butanol, hexanol,phenethylalcohol, benzylalcohol, phenylpropylalcohol,p-chlorobenzylalcohol, p-hydroxyphenethylalchol, etc.

The compounds according to the invention contain an asymmetric carbon atposition 2 of the tetracyclic molecule. Besides the racemate opticalantipodes are thus possible which also belong to the compounds accordingto the invention. These optical isomers are prepared from thecorresponding racemate by a resolution in the usual way. By resolving astarting product or an intermediate product in the synthesis, theoptical isomers can also be obtained in a direct way.

The pharmaceutically acceptable salts of the compounds I according tothe invention are acid addition salts and quaternary ammonium compounds.

The novel compounds of the formula I may be isolated from the reactionmixture in the form of a pharmaceutically acceptable acid addition salt,dependent upon the conditions in which the reaction is carried out. Theacid addition salts may also be obtained by treating the free base witha pharmaceutically acceptable organic or inorganic acid. Acids that canbe used in this connection are: hydrochloric acid, hydrobromic acid orhydroiodic acid, phosphoric acid, acetic acid, propionic acid, glycollicacid, maleic acid, malonic acid, succinic acid, tartaric acid, citricacid, ascorbic acid, salicyclic acid or benzoic acid.

The quaternary ammonium compounds and in particular the lower (1-4 C)alkyl quaternary ammonium compounds are obtained by reacting thecompounds of the general formula I with an alkyl halide, for examplemethyl iodide or methyl bromide.

It is possible as a matter of course to introduce or to modify thesubstituents at one or both phenyl nucleii even after the condensationreactions described before. Thus a hydroxyl group can be converted intoan alkoxy group, an amino group into a hydroxy- or halogen group, amethoxy group into a hydroxy group etc.

The unsubstituted or monosubstituted amines of the general formula I (R₅and/or R₆ = H) may be alkylated in the usual way, for example byreaction with an alkyl- or aralkylhalide. More common for this purposeis, however, the acylation of the nitrogen atom in question with, forexample, an acid chloride or anhydride followed by a reduction of thecarbonyl group of the N-acyl derivative thus obtained. For theintroduction of methyl groups at the nitrogen atom the procedureaccording to Eschweiler-Clarke (heating with a mixture of formaldehydand formic acid) or the reaction with formaldehyde andsodiumcyanoborohydride in a suitable solvent, such as acetonitril, ispreferred.

With an alkyl group with 1-6 carbon atoms is meant a branched orunbranced alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert.butyl, n.pentyl, isopentyl and hexyl.

The alkyl group in the alkoxy and alkylthio moieties has the samemeaning.

An aralkyl group mentioned in the definition of R₅ and R₆ is preferablya phenylalkyl group, in which the alkyl group contains 1-4 carbon atoms,such as benzyl, phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyland phenylisobutyl.

The heterocyclic 5- or 6-membered ring (definition of R₅ and R₆) mayeither be saturated or unsaturated, such as a pyrrolino group, apyrrolidino group, a piperidino group, an oxazolidino group, amorpholino group, a piperazine group, etc.

Amines according to the general formula V, that may be used in thevarious condensation reactions to obtain the compounds of the inventionare, for example ammonia, methylamine, dimethylamine, diethylamine,isopropylamine, dibutylamine, t.butylamine, benzylamine,phenylethylamine, phenylpropylamine, 2-phenyl-1-methyl-ethylamine,pyrroline, pyrrolidine, piperidine, oxazolidine, morpholine, piperazine,etc.

As already pointed out previously the compounds of the invention I exerta valuable central nervous system activity. This C.N.S. activity can beconcluded from the results of various pharmacological experiments, suchas the reserpine antagonism test, reserpine reversal test, aggressionisolated mice test, ambulation test, rotarod test, grip strength test,muricidal inhibition test, etc.

The surprising high activity of the compounds I in antagonizinghypothermia induced by reserpine (reserpine antagonism test) give strongindications that the present compounds can be used as antidepressants.

The compounds I may be administered both orally and parenterally,preferably in a daily dose of from 0.1 to 10 mg per kg bodyweight.

Mixed with suitable auxiliaries the present compounds can be compressedinto solid dosage units such as pills, tablets or coated tablets, orthey can be processed into capsules. With the aid of suitable liquidsthe compounds can be applied as injection preparations in the form ofsolutions, emulsions or suspensions.

Preferably compounds I and, in particular, compounds I A are used inwhich X stands for a methylene moiety (--CH₂ --) or a >N-alkyl moiety,in particular a >N--CH₃ moiety. Especially the latter type of compounds(X = >N-alkyl) excels in a very potent antidepressant activity.

Furthermore the compounds 1, in which n is 0 or 1 are to be preferredover the compounds I, having a longer side chain (n = 2).

In the Examples the following nomenclature and numbering has been used:##STR17##

By way of example the preparation of various starting products aredisclosed. The preparation of analogous starting products proceeds inexactly the same way.

PREPARATION STARTING MATERIALS 1.2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine

To a solution of 42 g of the compound10-keto-10,11-dihydro-dibenzo(b,f)-oxepine in 200 ml of dry ethanol asolution of sodiumethoxide (7 g of sodium in 500 ml of ethanol) is addeddropwise. After stirring the mixture for 30 minutes 16.2 ml ofmethylvinylketon in 50 ml of ethanol are added, whereupon the solutionis refluxed for 1 hour. The solution is cooled then and poured into 2 NHCl. After extracting into ether, washing the ether layer with water(till neutral) and drying the etherial phase, the solvent is evaporated.

The residue, a redcoloured oil, is chromatographed after that over analumina column and used for further conversion immediately. Yield: 37%oil.

In the same manner are prepared:

2-keto-11-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; meltingpoint 146°-147° C.

2-keto-11,12-dimethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; (oil).

2-keto-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; meltingpoint 107°-108° C.

2-keto-11-trifluoromethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;(oil).

2-keto-6-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; meltingpoint 128°-129° C.

2-keto-6-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; (oil).

2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine; (oil).

2-keto-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene; meltingpoint 132°-133° C.

2-keto-12-hydroxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;(oil).

2-keto-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;(oil).

2-keto-11-methyl-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;(oil).

2-keto-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;melting point 158°-163° C.

2-keto-12-trifluoromethyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;(oil).

7-keto-7-chloro-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;(oil).

2-keto-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine; (oil).

2-keto-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine; (oil).

2-keto-7-methoxy-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine;(oil).

2. 2-hydroxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine

6.2 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine are added toa suspension of 3.7 g of lithiumaluminiumhydride in 300 ml of dry ether.After refluxing for 2 hours 14.8 ml of water are added carefully. Thesuspension obtained is filtered off and after that the filtrate is driedand evaporated to dryness.

3. 2-hydroxy-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine

1.0 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine is added to asuspension of 10 mg PtO₂ (Adams catalyst) in 50 ml glacial acetic acid.The mixture is put in a hydrogenation apparatus under hydrogenatmosphere and shaken for 3 hours. After that time the theoreticalquantity of hydrogen has been absorbed. The mixture is then filtered toremove the catalyst, whereupon the filtrate is evaporated in vacuo,yielding a light yellow oil.

4. 2-mesyloxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine

6.2 g of 2-hydroxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine are addedto a mixture of 16.8 ml of pyridine and methane sulphonylchloride, afterwhich the mixture is stirred for 2 hours at 0° C. and then another 2hours at room temperature. After that the mixture is poured out intowater and then extracted with ether. The ether layers are dried andevaporated to dryness.

5. 2-azido-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine

The mesylate obtained in 3 in brought into a mixture of 25 ml ofdimethylformamide and 4.2 ml of water, to which 1.52 g of activatedsodium azide is added. The mixture is refluxed for 5 hours. Aftercooling the mixture is poured out into water and extracted with ether.After that the ether layers are washed dried, and evaporated to dryness.

6. 2-cyano-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine

2.62 g of the 2-hydroxy compound obtained in 2 is dissolved in 50 ml ofbenzene whereupon 5 g of phosphorus triiodide is added. The mixture isrefluxed for 2 hours. After cooling this mixture ice-water is cautiouslyadded. The organic layer is separated, washed with water and dried. Thesolvent (benzene) is then evaporated yielding 3.6 g of the oily2-iodo-compound. This residue is immediately dissolved in 300 mldimethylformamide, after which 4 g sodiumcyanide is added. The mixtureobtained is heated at 90° C. for 1 hour stirring all the time. Thereaction-mixture is then poured into 600 ml water and extracted withether. The crude nitrile is obtained after evaporation of the ether andimmediately used for further reactions.

7. 2-cyanomethylidene-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine

1 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine is mixed with 1ml of benzene, 15 ml of acetonitrile and 0.5 g of molecular sieve (4 A).50 mg of sodium-ethoxide are added and the mixture is heated for 3 hours(90°-100° C.). After cooling the mixture the molecular sieve is filteredoff and the filtrate evaporated.

EXAMPLE I 2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine

3.7 g of 2-azido-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine are added toa suspension of 3 g of lithiumaluminiumhydride in 100 ml of dry ether.The mixture is refluxed for 1 hour. After the mixture has been cooleddown, 12 ml of water are added carefully after which the mixture isstirred for some time. The suspension is filtered and after that thefiltrate is dried and evaporated to dryness. The residue is convertedwith maleic acid into the maleate. Melting point of the maleate:198°-202° C. Yield 85%.

EXAMPLE II

In the way indicated in example I are prepared:

2-amino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).

2-amino-7-chloro-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine,(oil).

2-amino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene; meltingpoint as maleate: 185°-188° C.

2-amino-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;melting point as maleate: 165° C. (dec.).

2-amino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;melting point as maleate: 196°-201° C.

2-amino-7-chloro-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene,(oil).

2-amino-11-trifluoromethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine,(oil).

2-amino-11-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; meltingpoint as maleate: 190°-192° C.

2-amino-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; meltingpoint as maleate: 194°-196° C.

2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine; melting pont asmaleate: 178°-180° C.

2-amino-12-trifluoromethyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene,(oil).

2-amino-12-hydroxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene,(oil).

EXAMPLE III2-dimethylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene

In a 500 ml Parr apparatus a mixture of 20 g2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-cycloheptatriene in 300 ml ofabsolute ethanol and a solution of 6 g of dimethylamine in 20 ml ofethanol to which 3.9 g of palladium 10% on charcoal are added, ishydrogenated by means of hydrogen under a pressure of 3 kg/cm².

The mixture is then filtered and the filtrate washed, dried andevaporated to dryness. The residue is an oily substance. The oil iscrystallized by means of maleic acid. Melting point afterrecrystallization from ether-ethanol 145°-150° C. and 169°-171° C.(double melting point).

Treatment of the free base with methyliodide resulted in the iodomethylate.

EXAMPLE IV 2-dimethylamino-6-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)oxepine

To a mixture of 10 ml of dimethylamine and 3.1 ml of 98% formic acid at-10° C. a solution of 11.5 g of2-keto-6-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine in 30 ml ofdimethylformamide are added dropwise. The mixture is refluxed for 10hours. After cooling, the mixture is poured into water and extractedinto ether. The ether layer is then washed with 300 ml of 2 N HCl. Theacidic water layer is made alkaline with 2 N NaOH, after which thealkaline aqueous solution is extracted with ether once more. The etherlayers are collected, dried and then evaporated. The oil obtainedcrystallizes as maleate: melting point 171° C.

EXAMPLE V2-dimethylamino-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene

500 mg of2-keto-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatrienein 2.7 ml of methanol is treated with 150 ml of sodiumborohydride and0.14 ml of methanolic HCl solution (5 N). After mixing for 10 hours atan elevated temperature, the reaction mixture is filtered and thefiltrate extracted with ether. The ether layer is washed, dried andevaporated. The oil obtained is then chromatographed over an aluminacolumn. Melting point as HCl salt: 210° C. Yield 30%.

EXAMPLE VI

In the way indicated in example III are prepared:

2-dimethylamino-7-methoxy-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine,(oil).

2-amino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene; meltingpoint as maleate: 183°-185° C.

2-methylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;melting point as maleate: 162°-165° C.

2-dimethylamino-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;melting point HCl salt: 210° C. (dec.).

2-dimethylamino-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;melting point maleate: 195°-196° C.

2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine; meltingpoint HCl salt: 250°-255° C. (dec.).

2-morpholino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine, (oil).

2-dimethylamino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine,(oil); maleate salt 212°-218° C.

2-methylamino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine,(oil).

2-piperidino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine,(oil).

2-benzylamino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine,(oil).

2-benzylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene,(oil).

2-phenethylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene,(oil).

2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiazepine, (oil); meltingpoint maleate: 178° C.

2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiazepine, (oil);melting point HCl salt: 250° C. (dec.).

2-dimethylamino-7-hydroxy-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine,(oil).

2-dimethylamino-9,12-dimethyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine,(oil).

2-dimethylamino-9-methyl-11-trifluoromethyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine,(oil).

EXAMPLE VII

In the way indicated in example IV are prepared:

2-dimethylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;melting point maleate: 145°-150° C. and 169°-171° C.

2-dimethylamino-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;m.p. HCl salt: 210° C.

2-dimethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;m.p. maleate: 198°-201° C.

2-dimethylamino-7-chloro-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene,(oil).

2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; meltingpoint maleate: 103°-108° C.

2-dimethylamino-11-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;melting point maleate: 140°-142° C.

2-dimethylamino-11,12-dimethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine,(oil).

2-dimethylamino-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;melting point maleate: 195°-196° C.

2-dimethylamino-6-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;melting point maleate: 182°-183° C.

2-dimethylamino-11-methyl-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene,(oil).

2-morpholino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene,(oil).

2-piperidino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine,(oil).

2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine; meltingpoint HCl salt: 250°-255° C.

2-dimethylamino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine;melting point maleate: 210°-220° C. (dec.).

2-dimethylamino-11-trifluoromethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine,(oil).

2-dimethylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine, (oil).

EXAMPLE VIII

In the way indicated in example V, the following compounds are prepared:

2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; melting pointmaleate: 198°-200° C.

2-methylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine, (oil).

2-morpholino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine, (oil).

2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; meltingpoint maleate: 105°-110° C.

2-dimethylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;melting point maleate: 145°-150° C. (and 168°-170° C.).

2-dimethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;melting point maleate: 198°-200° C.

2-dimethylamino-12-hydroxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene,(oil).

2-dimethylamino-11-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;melting point maleate: 138°-142° C.

2-amino-11-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine; meltingpoint maleate: 190°-193° C.

2-pyrrolidino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene,(oil).

2-diethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene;melting point maleate: 187°-192° C.

2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine; melting pointmaleate: 178°-180° C.

2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine; meltingpoint HCl salt: 250° C. (dec.).

2-dimethylamino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine;melting point maleate: 210°-228° C. (dec.).

2-dimethylamino-12-trifluoromethyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene,(oil).

EXAMPLE IX 2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine

1.7 g of 2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine is dissolvedin 47.2 ml of formic acid and 47.2 ml of a 40% solution of formaldehydein water. The mixture is heated at 100° C. for 5 hours after which themixture is cooled. The solution is then poured into water and madealkaline with diluted sodiumhydroxide. After that the mixture isextracted with ether and the ether layers obtained dried and evaporated.The oil obtained crystallizes with maleic acid as maleate: melting point103°-108° C. Obtained in this manner: 53%.

EXAMPLE X2-dimethylamino-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene

To a solution of 1 g of2-amino-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo-cycloheptatriene in 15ml of acetonitril, 2.7 ml of a 40% formaldehyde solution in water and660 mg of cyanoborohydride are added. The reaction is exothermic. Afterstirring for 1 hour 0.8 ml of acetic acid is added after which themixture is stirred for another 2 hours. The solution is made alkalineafter that and then extracted with ether. The ether layer is dried andevaporated. Melting point HCl salt: 210° C.

EXAMPLE XI2-dimethylaminoethyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene

22.50 g of triethylphosphonoacetate (prepared by means of theMichaelis-Arbuzow reaction) is added dropwise at 20° C. to a slurry of50% sodium hydride (4.9 g) in 200 ml of dry 1,2-dimethoxy-ethane. Afteraddition the reaction mixture is stirred for 1 hour at room temperatureuntil gas evolution ceased. Then 26 g of2-keto-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene is addedslowly at such a rate that the temperature is maintained below 40° C.After an additional quarter of an hour the mixture is poured into alarge excess of water and the aqueous solution extracted with ether. Theether layer after being dried over sodiumsulphate and evaporated gives26.0 g of2-ethoxycarbonylmethyl-3,4-dihydro-9H-tribenzo(b,d,f)-cycloheptatriene.

Catalytic hydrogenation of 15 g of this product in methanol andpalladium/charcoal-catalyst gives the 1,2,3,4-tetrahydro-compound. Afterevaporation of the methanol to a volume of 70 ml, the mixture is treatedwith 30 g of dimethylamine in an ampoule at 100° C. for 14 hours to givethe 2-dimethylamino-carbonylmethyl-compound, 13.5 g. This product isreduced with 15 g lithiumaluminiumhydride in ether (8 hours at boilingtemperature) in the usual manner yielding 13.0 g of the title compound.The oily residue is converted to the maleate, melting point 131°-133° C.

The same product is obtained by carrying out the hydrogenation withpalladium on charcoal in the last step of the synthesis instead ofperforming this hydrogenation previous to the amide formation andsubsequent reduction of the amide moiety with LiAlH₄.

In the same manner are prepared:

2-dimethylaminoethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepineand

2-aminoethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.

EXAMPLE XII2-aminomethyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene

1.4 g of the 2-cyano-compound, prepared in a similar manner as described(see "starting materials" 6) is dissolved in 50 ml tetrahydrofuran afterwhich 1.5 g LiAlH₄ is added. The mixture is boiled for 4 hours. Aftercooling 12 ml of water is added slowly while stirring. Filtration andevaporation of the solvent yields 2.4 g of the 2-aminomethyl-compound asan oil. Melting point maleate salt: 125°-132° C.

In the same manner are prepared:

2-aminomethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.

2-aminomethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine.

2-aminomethyl-7-methoxy-10-chloro-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene.

EXAMPLE XIII2-dimethylaminomethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine

1.5 g of 2-cyano-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine ("startingmaterial 6") is suspended in 80 ml diethyleneglycol and 65 ml of anaqueous KOH solution (40%). The mixture is refluxed for 5 hours. Aftercooling the mixture to ambient temperature, it is poured into 450 mlwater. The aqueous mixture is extracted with ether to remove non-acidicmaterial. The water-phase is acidified to about pH 3, whereupon themixture is extracted with ether. The ether extracts are washed, driedand then evaporated, yielding 0.80 g of the crude2-carboxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine. Thiscarboxyl-compound is converted into the dimethylamide in the usualmanner and then reduced with LiAlH₄, yielding 0.5 g of the title productas an oil.

In the same manner are prepared:

2-dimethylaminomethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine,(oil).

2-dimethylaminomethyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene,(oil).

2-aminomethyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene,(oil).

2-benzylaminomethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine,(oil).

EXAMPLE XIV2-aminoethyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene

Diborane gas, obtained from 1.2 g of NaBH₄ and 5.2 ml of BF₃ -etherateis let in into a solution of 200 mg of2-cyanomethylidene-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene(obtained in a similar manner as described in "Starting materials" 7) in15 ml THF under nitrogen atmosphere.

After that the mixture is refluxed for 1 hour. The excess of B₂ H₅present is then decomposed by adding ethanol, whereupon the solution isevaporated.

The residue is dissolved in 18 ml of a mixture of concentrated HCl andwater (1:1) whereupon the solution is heated for some time. The acidicwater layer is cooled down, made alkaline and then extracted into ether.Evaporating the solvent yields 85 mg of the title compound as an oil.

In the same manner as prepared:

2-aminomethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.

2-aminomethyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine.

EXAMPLE XV2-amino-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatriene

10 g of 2-keto-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene issuspended in 400 ml of ethanol and subsequently 20 g hydroxylamine.HCland 40 ml pyridine are added. After refluxing the mixture for 30minutes, the mixture is concentrated to a thin oil in vacuo, from whichthe oxime crystallized slowly. The precipitate is sucked off and washedwith water. The dried oxime is suspended in isopropanol. Over a periodof 3 hours 20 g sodium are added while stirring. The reaction mixture isconcentrated to one-fourth of its volume by evaporation (Rotavap) andthen diluted with water and extracted with ether. The ether extract wasdried over anhydrous potassium carbonate and finally evaporated todryness. The oil obtained is converted into its maleate, melting point212°-213° C. Yield 7.3 g.

In the same way are prepared:

2-amino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine and

2-amino-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-azepine.

By using palladium on charcoal (10%) the oxime is hydrogenated into the4a,13b-unsaturated compound:2-amino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene, (oil);melting point maleate: 181°-186° C.

EXAMPLE XVI2-dimethylamino-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatriene

4 g of the primary amine prepared according to example XV is methylatedwith a formaldehyde/formic acid mixture (1:1) during 5 hours at 100° C.,(Clarke-Eschweiler procedure). Obtained is 4.2 g of the dimethylaminoproduct which is converted to its hydrochloride, melting point 256°-263°C.

EXAMPLE XVII2-dimethylamino-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatriene

In the same manner as described in Example IV the compound2-keto-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatriene,obtained by oxydation of the corresponding alcohol with chromic acid inbenzene, acetic acid, water at room temperature, is reacted withdimethylamine and formic acid in dimethylformamide at refluxtemperature. Melting point HCl salt 260°-263° C.

The same product is obtained by converting2-hydroxy-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatriene,obtained by hydrogenating the corresponding2-keto-1,2,3,4-tetrahydro-compound with PtO₂ in glacial acetic acid,into2-mesyloxy-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatrienein the same manner as described in "starting materials" 3 and 4 andtreating this mesyloxy compound with dimethylamine.

In the same manners are prepared:

2-dimethylamino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine.

2-dimethylamino-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-azepine.

2-dimethylamino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-thiazepine.

2-dimethylamino-12-methyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatriene.

2-methylamino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine.

2-dimethylamino-7-methoxy-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-azepine.

2-morpholino-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-azepine.

EXAMPLE XVIII2-carboxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene

In the manner described in example XIII 2.3 g2-cyano-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene ishydrolysed into the corresponding 2-carboxy-compound. Recrystallizationfrom benzene gives 1.2 g of the pure carboxy-compound; melting point196°-202° C., which is then converted into the methyl-, butyl-, benzyl-and phenethylester.

In the same way are prepared:

2-carboxy-7-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene.

2-carboxy-7-methoxy-10-chloro-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene.

2-carboxy-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine and thecorresponding 7-methoxy compound.

2-carboxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiazepine.

2-carboxy-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene.

EXAMPLE XIX2-carboxymethyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene

10 g of the ethoxycarbonylmethyl-compound obtained in the example XI isheated in a mixture of 15 g of potassium hydroxide, 10 ml of water and200 ml of ethanol for 2 hours at boiling temperature. The mixture isconcentrated in vacuo to about 50 ml, diluted with water and acidifiedto pH 3 with hydrochloric acid. Extraction with benzene and evaporationof the solvent gives 9.5 g of the title compound.

In the same manner is prepared:

2-carboxymethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene.

EXAMPLE XX2-aminomethyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatriene

2-hydroxy-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatrieneis converted into the corresponding 2-mesyloxy compound in the samemanner as described in "starting materials" 4 and then treated withsodiumcyanide, to obtain the 2-cyano-compound. This compound isimmediately reduced with LiAlH₄ in ether as described previously,yielding the 2-aminomethyl-compound as an oil.

Conversion of this oil with maleic acid yields the maleate; meltingpoint: 128°-132° C.

In the same manner is prepared:

2-aminomethyl-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-azepine.

I claim:
 1. A compound of the formula: ##STR18## or a pharmaceuticallyacceptable salt thereof, in which X represents the group consisting ofoxygen and sulphur,R₁, r₂, r₃ and R₄ are selected from the groupconsisting of hydrogen, hydroxy, halogen, alkyl having 1 to 6 carbonatoms, alkoxy having 1 to 6 carbon atoms, alkylthio having 1 to 6 carbonatoms and trifluoromethyl, R₅, r₆ are selected from the group consistingof hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl having 7 to 10carbon atoms, and together in combination with the nitrogen atom amorpholine ring, n is selected from 0, 1 and 2, and the dotted linesignifies an optional bond.
 2. A compound according to claim 1 of theformula I A: ##STR19## in which R₁, R₂, R₃, R₄, R₅, R₆, X and n have themeanings indicated in claim
 1. 3. A compound of the formula I accordingto claim 1 in which n is the number 0 or
 1. 4. The compound of claim 1wherein R₆ is selected from the group consisting of hydrogen and alkylhaving 1 to 6 carbon atoms.
 5. The compound of claim 1 which is2-dimethylamino-1,2,3,4-tetrahydro-tribenzo-(b,d,f)-oxepine.
 6. Thecompound of claim 1 which is2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
 7. The compound ofclaim 1 which is2-amino-11-trifluoromethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.8. The compound of claim 1 which is2-amino-11-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
 9. Thecompound of claim 1 which is2-amino-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
 10. Thecompound of claim 1 which is2-dimethylamino-6-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine. 11.The compound of claim 1 which is2-dimethylamino-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.12. The compound of claim 1 which is2-dimethylamino-11-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.13. The compound of claim 1 which is2-dimethylamino-11,12-dimethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.14. The compound of claim 1 which is2-dimethylamino-6-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine. 15.The compound of claim 1 which is2-dimethylamino-11-trifluoromethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.16. The compound of claim 1 which is2-methylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
 17. Thecompound of claim 1 which is2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
 18. Thecompound of claim 1 which is2-aminoethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
 19. Thecompound of claim 1 which is2-aminomethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
 20. Thecompound of claim 1 which is2-dimethylaminomethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine. 21.The compound of claim 1 which is2-amino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine.
 22. Thecompound of claim 1 which is2-dimethylamino-1,2,3,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine.
 23. Thecompound of claim 1 which is2-methylamino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine.
 24. Thecompound of claim 1 which is2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine.
 25. The compound ofclaim 1 which is2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine.
 26. Thecompound of claim 1 which is2-morpholino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
 27. Thecompound of claim 1 which is2-morpholino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine.